Abstract

Chronic liver injury characterized by unresolved hepatitis leads to fibrosis,potentially progressing to cirrhosis and hepatocellular carcinoma. Effectivetreatments for halting or reversing liver fibrosis are currently lacking. Thisstudy investigates the potential of HDAC6 as a therapeutic target in liverfibrosis. We synthesized two selective HDAC6 inhibitors, DR-3 andFDR2, and assessed their effects on hepatic stellate cell (HSC) activationand liver fibrosis using human precision cut liver slices (hPCLS). Moleculardocking, deacetylation inhibition assays, and various cellular assays wereemployed to evaluate the specificity and anti-fibrotic efficacy of these inhib-itors. DR-3 and FDR2 demonstrated high selectivity for HDAC6 overHDAC1, significantly inhibiting HSC activation markers and fibrogenicgene expression. Both inhibitors increased acetylation of a-tubulin and sup-pressed TGF-b1-induced SMAD signaling in HSCs. In human precisioncut liver slices (hPCLS), DR-3 and FDR2 reduced fibrogenic protein levelsand collagen deposition. The selective inhibition of HDAC6 by DR-3 andFDR2 effectively reduces HSC activation and fibrogenesis in liver models,supporting further investigation of HDAC6 inhibitors as potential anti-fibrotic therapies